cis-diamineplatinum (II) complexes containing phosphono carboxylate ligands as antitumor agents.
A series of platinum complexes of the form cis-M[PtA2(PC)] (I) has been prepared and tested for antitumor activity in mice. Compounds in this series contain either two monodentate amine ligands (A), such as NH3 or isopropylamine, or one bidentate diamine (A2), such as ethylenediamine, 1,2-diaminopropane, or 1,2-diaminocyclohexane. The PC ligand is a bidentate, O-bound, phosphono carboxylate chelate of the form -O2C(CR1R2)nPO3-, where n = 0 or 1 and R1 and R2 are chosen from H, methyl, ethyl, propyl, butyl, phenyl, or pentanoic acid substituents. The resulting complexes (I) were prepared as the free acids (M = H) or as sodium salts (M = Na). Members of this series have demonstrated good activity in a number of tumor screens. A total of 18 platinum-phosphono carboxylate (Pt-PC) complexes were tested against Sarcoma 180 ascites (S180a) in CFW mice, with 13 analogues showing activity above the 50% ILS level. Antitumor activity was also observed vs L1210 leukemia in CDF1 mice, where six of the 12 compounds tested gave ILS values in the 60-160% range, and vs M5076 reticulum cell sarcoma (sc tumor, iv drug), where four of the four compounds tested gave ILS and T-C values comparable to that of cisplatin. Each of the Pt-PC complexes was characterized by NMR (195Pt, 13C, and 31P), HPLC, and elemental analysis. These compounds, which are anionic at neutral pH, display excellent solubility and stability in aqueous media, such as phosphate-buffered saline and fetal calf serum. On the basis of a comparative study of BUN and serum creatinine levels in treated mice, representative complexes from this series are also less kidney toxic than cisplatin. The results of these studies demonstrate that the platinum-phosphono carboxylate complexes are a promising new class of antitumor agents.
Hollis
L S
LS
Eagelhard Corporation, Research and Development, Menlo Park CN-40, Edison, New Jersey 08818.
Miller
A V
AV
Amundsen
A R
AR
Schurig
J E
JE
Stern
E W
EW
D000818:Animals; D000970:Antineoplastic Agents; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000633:toxicity; D005260:Female; D006207:Half-Life; D007674:Kidney Diseases / Q000139:chemically induced; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis / Q000627:therapeutic use* / Q000633:toxicity; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000627:therapeutic use* / Q000633:toxicity; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use / Q000633:toxicity; D012510:Sarcoma 180 / Q000188:drug therapy; D012513:Sarcoma, Experimental / Q000188:drug therapy
D000970:Antineoplastic Agents; D063065:Organophosphonates; D009944:Organoplatinum Compounds; D010746:Phosphonoacetic Acid; D002945:Cisplatin